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【结 构 式】 
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【分子编号】16862 【品名】triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane 【CA登记号】160194-28-5 |
【 分 子 式 】C16H34OSi2 【 分 子 量 】298.61636 【元素组成】C 64.36% H 11.48% O 5.36% Si 18.81% |
合成路线1
该中间体在本合成路线中的序号：(III)1) The iodination of 4-(1,2,4-triazol-1-ylmethyl)aniline (I) with ICl and CaCO3 in methanol/water gives the 2-iodoaniline (II), which is cyclized with 1-(triethylsilyl)-4-(triethylsilyloxy)-1-butyne (III) by means of paladium acetate and Na2CO3 in hot DMF yielding 5-(1,2,4-triazol-1-ylmethyl)-3-[2-(triethylsilyloxy)ethyl]-1H-indole (IV). The desilylation of (IV) with HCl in methanol affords the corresponding alcohol (V), which is condensed with dimethylamine by means of methanesulfonyl chloride and triethylamine to give MK-0462 free base (VI). Finally, this compound is treated with benzoic acid in isopropyl alcohol/isopropyl acetate solution.
| 【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676. |
| 【2】 Lieberman, D.R.; Reamer, R.A.; Reider, P.J.; Cottrell, I.F.; Chen, C.-Y.; Verhoeven, T.R.; Larsen, R.D.; Houghton, P.G.; Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction. Tetrahedron Lett 1994, 35, 38, 6981-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 | |
| (I) | 16860 | 4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine | C9H10N4 | 详情 | 详情 | |
| (II) | 16861 | 2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine; 2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)aniline | C9H9IN4 | 详情 | 详情 | |
| (III) | 16862 | triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane | 160194-28-5 | C16H34OSi2 | 详情 | 详情 |
| (IV) | 16863 | 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl triethylsilyl ether; 5-(1H-1,2,4-triazol-1-ylmethyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indole | C19H28N4OSi | 详情 | 详情 | |
| (V) | 16864 | 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanol | C13H14N4O | 详情 | 详情 | |
| (VI) | 16865 | N,N-dimethyl-2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanamine; N,N-dimethyl-N-[2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl]amine | C15H19N5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Halogenation of the substituted aniline (VII) by means of iodine monochloride gave ortho-iodoaniline (VIII). 3-Butyn-1-ol (IX) was protected as the 1,4-bis(triethylsilyl)derivative (X) by deprotonation with butyllithium, followed by treatment with triethylsilyl chloride. Palladium-catalyzed condensation of disilylated butynol (X) with iodoaniline (VIII) furnished a mixture of the bis(silylated) tryptophol (XI) and the O-desilylated analogue (XII). Treatment of the crude mixture with methanolic HCl produced the completely desilylated indole (XIII), which was converted to mesylate (XIV) by reaction with methanesulfonyl chloride and triethylamine. Alkylation of pyrrolidine (VI) with mesylate (XIV) then yielded the target (indolylethyl)pyrrolidine, which was finally converted to the title dioxalate salt.
| 【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677. |
| 【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 34465 | N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (VI) | 34470 | 2-(5-[[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl]-1H-indol-3-yl)ethyl methanesulfonate | C15H18N2O5S | 详情 | 详情 | |
| (VII) | 15345 | (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one | C10H12N2O2 | 详情 | 详情 | |
| (VIII) | 34466 | (4S)-4-(4-amino-3-iodobenzyl)-1,3-oxazolidin-2-one | C10H11IN2O2 | 详情 | 详情 | |
| (IX) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (X) | 16862 | triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane | 160194-28-5 | C16H34OSi2 | 详情 | 详情 |
| (XI) | 34467 | (4S)-4-[(2-(triethylsilyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indol-5-yl)methyl]-1,3-oxazolidin-2-one | C26H44N2O3Si2 | 详情 | 详情 | |
| (XII) | 34468 | (4S)-4-[[3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C20H30N2O3Si | 详情 | 详情 | |
| (XIII) | 34469 | (4S)-4-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C14H16N2O3 | 详情 | 详情 |